It has long been known that a number of steroids have pharmacological effects as anesthetics. Reference is made e.g. to Selye, Anesthetic effects of steroid hormones, Proc Soc Exp Biol Med Vol 46, 116-121 (1941). However, many such components which have been tested have proved to suffer from undesirable properties causing side effects which have prevented clinical use of the steroids studied. The solubility characteristics of such compounds have caused problems which have proved difficult to overcome. In particular, many of these compounds are highly lipophilic, which has contributed greatly to the problems in preparing stable, clinically useful formulations for intravenous use.
The anesthetic properties of pregnanolone were first described by Figdor et al, Central activity and structure in a series of water-soluble steroids, J Pharm Exp Therap Vol 119, 299-309 (1957). In this paper, the aim was to overcome the administration-detoxification problem of the known steroids with anesthetic activity by conversion to water-soluble ester derivatives, which thus would be suitable for intravenous administration (Figdor et al loc cit p 300). The substances were tested in aqueous suspension containing methyl cellulose as suspending agent. However, the results were not successful.
Gyermek, in his paper "Pregnanolone: A Highly Potent, Naturally Occurring Hypnotic-Anesthetic Agent" Proc Soc Exp Biol Med Vol 125, 1058-1062 (1967) described animal studies using pregnanolone dissolved in propylene glycol. Since such preparations are not suitable for clinical use, no suggestions are given how to solve the problem of obtaining pregnanolone in a clinically acceptable and stable administration formula.
Three steroids have been used clinically as anesthetics, but none of these is currently being used. The compound 21-hydroxypregnan-3,20-dione, also known as hydroxydione and under the trade name Viadril, was introduced in 1955. Reference is made to Laubach et al, Steroid anesthetic agent, Science Vol 122, 78 (1955). Because of several disadvantages it was withdrawn. The compound 3alphahydroxy-5alpha-pregnan-11,20-dione, was put on the market under the trade name Althesin. Reference is made to Atkinson et al, Action of some steroids on the central nervous system of the mouse, J Med Chem Vol 8, 426-432 (1965), and to British patent specifications 1317184 and 1379730. This substance was brought into solution by adding the less active 21-acetate and a co-solvent, a non-ionic surface active polyoxyethylated castor oil available under the trade name Cremophor-EL. Also this steroid product was, however, withdrawn because of serious side effects.
The third steroid anesthetic product, minaxolone, was subjected to clinical evaluation in 1979. It was withdrawn because of problems with its toxicology profile.
In summary, the original screening studies in experimental animals, from which studies the animals were not allowed to survive were carried out using three types of pharmaceutical formulations:
1. ex tempore solutions in warm peanut or sesame oil which were injected as supersaturated solutions after being cooled to body temperature and sometimes containing a precipitate of crystalline material,
2. ex tempore aqueous suspensions prepared in roller mills with cellulose derivatives as thickening agents,
3. solutions in tissue irritating propylene glycol.
The exploratory synthetic chemistry which followed these studies was directed towards derivatives such as acetates, semisuccinates having higher water solubility than the parent compounds and also having the ability to form sodium salts. These derivatives must be hydrolyzed by the body before exerting the clinical effect, giving an unacceptable slow onset of action.
As described above this direction of research did not result in clinically acceptable formulations.
There is accordingly a great need for a clinically useful effective steroid anesthetic product which can be brought into an administration formula which is stable and suitable for intravenous administration. The present invention provides such a composition comprising an emulsion of pregnanolone.